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Can a modest change in regulation of NOD1 expression have a major impact on inflammation and gastric cancer?

Award Number: R21AI138258
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Altered protein dosage by defects in single genes leads to haploinsufficiencies and monogenic disorders, but the impact of small changes in gene expression on multifactorial disease is unknown. We have observed that a persistent small increase in expression of NOD1 (Nucleotide-binding oligomerization domain-containing protein 1), a key innate sensor of bacterial infection, precipitates a large physiological effect with dramatically altered cellular function associated with carcinogenesis. An approximately 1.1 to 1.2 fold increase in NOD1 protein concentration (~1.5 fold increase in NOD1 mRNA) leads to ligand-independent, switch-like NOD1 activation. Tight control of NOD1 expression plays a crucial role in limiting the development of an inflammatory state appears to be impaired in gastric adenocarcinoma with a small increase in NOD1 being associated with greater early patient mortality. In this proposal, we will investigate the regulatory circuit(s) that tightly control expression of NOD1 to prevent this sensor from exceeding a physiological switching checkpoint that promotes persistent inflammation and lethal cancer progression. We will conduct these investigations in the following specific aims: 1) To identify the mechanism(s) that control NOD1 expression and activation; 2) To understand if regulatory control of NOD1 is disrupted in gastric cancer patients and how a small increase in NOD1 expression promotes gastric cancer. Our investigations will reveal the impact of a single and modest cellular alteration on cancer, and will have broader implications for understanding how small expression changes caused by genetic variation impact development of complex diseases like autoimmunity and cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = -$39 )
2021	2019	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	2/5/2021	NON-COMPETING CONTINUATION	-$39
														Subtotal = -$39

Issue Date FY: 2019 ( Subtotal = $236,355 )
2019	2019	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	5/10/2019	NON-COMPETING CONTINUATION	$236,355
														Subtotal = $236,355

Issue Date FY: 2018 ( Subtotal = $286,426 )
2018	2018	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	5/18/2018	NEW	$286,426
														Subtotal = $286,426

Grand Total All Awards = $522,742

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Can a modest change in regulation of NOD1 expression have a major impact on inflammation and gastric cancer?

Award Number: R21AI138258

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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